synthesis, characterization and cytotoxic evaluation of ...€¦ · the development of new...

IOSR Journal of Pharmacy and Biological Sciences (IOSR-JPBS)

e-ISSN: 2278-3008, p-ISSN:2319-7676. Volume 9, Issue 5 Ver. IV (Sep -Oct. 2014), PP 42-48 www.iosrjournals.org

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Synthesis, characterization and cytotoxic evaluation of novel

derivatives of 1, 3, 4-oxadiazole containing 5-phenyl thiophene

moiety.

VinayakAdimule1,4

, SudhaMedapa2, AdarshaHaraballiJagadeesha

3,

LalitaSanjeev Kumar 4, Prakash Kumar Rao

1*

1Mount Carmel Centre for Scientific Research and Advanced Learning, Mount Carmel College, Vasanthnagar,

Bengaluru-560 052, Karnataka, India 2Department of Chemistry, Mount Carmel College (Autonomous),Vasanthnagar, Bengaluru- 560 052,

Karnataka, India. 3Inorganic and Physical Chemistry, IISc, Bengaluru, Karnataka, India.

4Department of Chemistry, School of Sciences, IGNOU, New-Delhi, India.

Abstract: In the present work a series of novel derivatives of 1,3,4-oxadiazoles containing 5-phenyl thiophene

moiety has been synthesized by convergent synthetic method and studied their anticancer properties. The

synthesized compounds were characterized by spectral (1H-NMR, 13C NMR, MS and elemental) analyses. Three

cell lines were used for thecytotoxic evaluation namely, HepG2, Caco-2 and PANC-1. The synthetic chemistry involved conversion of various substituted aromatic acids into ethyl ester 2a-e. The ethyl ester was converted

into corresponding carbohydrazide 3a-e. Carbohydrazides3a-e were reacted with 5-phenyl thiophene-2-

carboxaldehyde(5) in presence of acetic acid as catalyst and obtained novel Schiff base compounds6a-e. The

Schiff base derivatives were cyclized using chloramine-T as promoter and obtained novel derivatives of 1,3,4-

oxadiazole 7a-e.Among the synthesised compounds, the cytotoxicity of the compound 7b i.e. 2-(4'-

fluorobiphenyl-3-yl)-5-(5-phenylthiophen-2-yl)-1,3,4-oxadiazole against Caco-2 cell line with IC50 of 5.3µM.

The compound 7e i.e.2-(4-methoxyphenyl)-5-(5-phenylthiophen-2-yl)-1,3,4-oxadiazoleshowed moderate

cytotoxicity against HepG2 with IC50 of 28.4µM. Rest of the compounds showed less cytotoxicity against all the

three cell lines. Key words: PANC-1, Cytotoxicity, 1,3,4-oxadiazole, 5-phenylthiophene, Anticancer

I. Introduction The development of new anticancer therapeutic agents is one of the fundamental goals in medicinal

chemistry. In recent years there has been a concerned search for the discovery and development of potent and

selective anticancer agents. The various derivatives of 1,3,4-oxadiazoles substituted with different groups

displayed wide spectrum of biological activities such as anti-inflammatory[1] , antimicrobial[2], analgesic[3]anti-

tuberculosis[4], anticancer[5, 6, 7, 8] properties. Author envisage that by introducing 5-phenyl thiophene moiety into the 1,3,4-oxadiazole[9] ring system(Fig. 1) would produce the synergetic effect and increases the water solubility

and total polar surface area. The synthetic chemistry involved converting suitably substituted aromatic acid into

corresponding ethyl ester 2a-e. Ethyl ester was further converted into carbohydrazide 3a-e. The carbohydrazides

were reacted with 5-phenyl thiophene[10, 11](5) and obtained novel Schiff base[12, 13] compounds 6a-e.The Schiff

base compounds were cyclized using chloramine-T[14] and obtained novel derivatives of 1,3,4-oxadiazole 7a-

e(Fig. 1).The key intermediate 5-phenyl thiophene carbohydrazide(5) and 1,3,4-oxadiazole and related

compounds have been described as useful building blocks for the synthesis of various heterocyclic rings. A

series of 5-phenylthiophene of 1,3,4-oxadiazole[15]derivatives7a-e(Fig. 1)have been synthesized and tested their

cytotoxicity on human cancer cell lines[. Notably, the halogen substitutions were incorporated to improve the

solubility of the compounds. Author envisaged that by making Schiff base compounds of various halogens

substituted aromaticcarbohydrazides with 5-phenylthiophene moiety and cyclizing the Schiff base[16] compounds using chloramine-T as promoter improves the total polar surface area and increases the water

solubility. All the final compounds were characterized by spectral (1H-NMR, 13CNMR, MS and elemental)

analyses. Thus it was of interest to implement drug design and to synthesise the novel candidates by joining the

5-phenyl thiophene with different halogen substituted aromatic carbohydrazides and obtained novel derivatives

of 1,3,4-oxadiazoles.

Synthesis, characterization and cytotoxic evaluation of novel derivatives of 1, 3, 4-…..


N

O

N SR1

R4

R3

R2

R1, R2, R3 and R4 are different

substituions

1.1 Figure 1: General structures of the 5-phenylthiophene containing 1,3,4-oxadiazole moiety

II. Experimental: 2.1 Materials and Methods:All the reagents, chemicals and solvents were purchased from S-d fine and

Spectrochem Ltd, Bengaluru, India.1H-NMR and 13C-NMR were recorded by Brucker 400 MHz

spectrophotometer. Melting points are determined using Buchi melting point 545. Mass spectra were recorded

by Agilent 1200 series. TLC was done using F254 grade silica 60 from Merck.IR spectra was recorded by FTIR

1800 series. Whirlpool microwave (genius) was used for microwave reaction.

2.2 Synthesis:

2.2.1 General procedure for synthesis of aromatic ethyl ester2a-e:

To a mixture of acid 1a-e (1mol, 1equivalent), ethyl alcohol (50mL) and conc.H2SO4 were refluxed at

85°C for 6-8h. Progress of the reaction was monitored by TLC (thin layer chromatography), which indicated

completion of the reaction. Ethyl alcohol was completely removed, residue was extracted with ethyl acetate (20 × 3mL), washed with brine (10mL) and dried over Na2SO4. Ethyl acetate was concentrated under reduced

pressure and obtained colourless syrup. The structure was confirmed by spectral and analytical data.

2.2.2General procedure for synthesis of aromatic carbohydrazide3a-e:

To a solution of 2a-e in ethyl alcohol (50mL) was added with excess of hydrazine hydrate and refluxed

at 80°C for 10-12h. Progress of the reaction was monitored by TLC, indicated completion of the reaction.

Reaction mixture was concentrated completely under reduced pressure, ice pieces were added and stirred.

Precipitate formed was filtered and dried. The structure was confirmed by spectral and analytical data.

2.2.3 Synthesis of 5-phenyl thiophene-2-carboxaldehyde (5):

To a mixture of 5-bromothiophene-2-carboxaldehyde(2g, 0.0104mol1 equivalent), phenyl

boronicacid(1.405g, 0.0115mol), Na2CO3(2.2g, 0.0208mol), tetrakis (triphenylphosphine) palladium(0)(606mg, 0.052mmol) and ethyl alcohol(100mL) were refluxed at 85°C for 10h.Progress of the reaction was monitored by

TLC, which indicated the completion of the reaction. Ethyl alcohol was completely removed, residue was

extracted with ethyl acetate(25mL×3), washed with brine(10mL) and dried over Na2SO4. The crude product was

purified by column-chromatography (silicagel100-200mesh),ethylacetate inhexane(0-15%) as eluent. Yield =

1.85g; m.p-98-123°C; 1H-NMR (CDCl3, 400MHz): δ 7.45 (dd, 2H), 7.52 (m, 3H, J = 12.8Hz), 7.62 (d, 2H, J =

6.8Hz), 7.67 (d, 1H), 8.8(s, 1H); 13CNMR (CDCl3, 100MHz): 125.5, 126.5, 127, 129, 132, 136, 138, 141, 192.

2.2.4 General procedure for synthesis of Schiff base derivatives 1,3,4-oxadiazole containing 5-

phenylthiophene6a-e:

To a mixture of carbohydrazide 3a-e, acetic acid(2-5drops) and 5-phenylthiophene-2-carboxaldehyde

(5) (1.1 mmole) were refluxed at 85°C for 2-3h. Progress of the reaction was monitored by TLC, indicated the completion of the reaction. Reaction mixture was concentrate under reduced pressure, ice cold water was added

and the precipitate formed was filtered, dried. The structure was confirmed by spectral and analytical methods.

2.2.5 General procedure for synthesis 5-phenylthiophene substituted 1,3,4-oxadiazoles 7a-e:

To a solution of the compound 6a-e (1mmol) ion ethyl alcohol (5mL) and Chloramine-T(1.1mmol) was

irradiated with microwave for 60 seconds. Progress of the reaction was monitored by TLC, indicated completion

of the reaction. Reaction mixture was extracted with ethyl acetate(25mL × 3), washed with brine(10mL) and

dried over Na2SO4. The crude product was purified by column-chromatography (silicagel100-

200mesh),ethylacetate inhexane(0-75%) as eluent.



2.3 Analytical data of the compounds 7a-e:

2.3.1 2-(2,5-Dimethoxy-phenyl)-5-(5-phenyl-thiophen-2-yl)-[1,3,4]oxadiazole (7a):

Pale yellow solid; Yield 45%; m. p 103-1060C;1H- NMR (400MHz, CDCl3): δ 3.85 (s, 3H, OCH3), 3.95 (s, 3H, OCH3), 7.0195 (d, 1H, J = 9.2, Ar-H), 7.082 (dd, 1H, J = 12Hz), 7.298 (d, 3H, J = 8Hz), 7.374 (t, 1H, J =

7.2Hz), 7.435(t, 1H, J = 14.8Hz), 7.534(d, 1H, J = 3.2Hz), 7.675(t, 1H, J = 8.4Hz), 7.799( q, 3H, J = 14.8Hz); 13C-NMR (CDCl3, 100MHz): 21.6, 56.5, 77.16, 113.5, 114.7, 119.4, 124, 126.35, 128.8, 129.53, 130.8, 133.2,

139.3, 143.6, 149.3, 152.4, 153.6, 160.7, 162.7; IR (KBr, cm-1) (C-H) 2935, (CH, w) 3322, (C-O) 1180, (C-F)

874, (C-S) 1151 (CH2) - 2765, (NH) 3320; MS(ESI) m/z : 365 [M+H] +; anal. Calculated for C20H16N2O3S; C,

65.92; H, 4.43; N, 7.69; O, 13.17; S, 8.80; found C, 65.96; H, 4.47; N, 7.70; O, 13.18; S, 8.82.

2.3.2 2-(4'-Fluoro-biphenyl-3-yl)-5-(5-phenyl-thiophen-2-yl)-[1,3,4]oxadiazole(7b):

Off white solid; Yield 76%; m. p 112-1160C;1H- NMR (400MHz, CDCl3): δ 7.374 (q, 2H, J = 15.2Hz), 7.439

(q, 3H, J = 16.8Hz), 7.502 (t, 2H, J = 14.8, Ar-H), 7.610 (t, 1H, J = 15.6Hz), 7.676 (d, 4H, J = 7.6Hz), 7.78 (d,

1H, J = 8Hz), 7.822 (d, 1H, J = 4Hz), 8.104 (d, 1H, J = 8Hz), 8.349 (s, 1H) ; 13C-NMR (CDCl3, 100MHz): 77.6, 123.9, 124.27, 125.7, 126.3, 127.3, 128.5, 129.2, 130.7, 133.24, 140, 142.4, 149.5; IR (KBr, cm-1) (C-H) 2975,

(CH, w) 3342, (C-O) 1185, (C-F) 883, (C-S) 1131 (CH2) - 2785, (NH) 3370; MS(ESI) m/z : 399 [M+H] +; anal.

Calculated for C24H15FN2OS; C, 72.34; H, 3.79; F, 4.77; N, 7.03; O, 4.02; S, 8.05; found C, 72.35; H, 3.81; F,

4.79; N, 7.05; O, 4.05; S, 8.07.

2.3.3 2-Biphenyl-3-yl-5-(5-phenyl-thiophen-2-yl)-[1,3,4]oxadiazole(7c):

Pale yellow solid; Yield 66%; m. p 132-1330C; 1H- NMR (400MHz, CDCl3): δ 7.386 (t, 2H, J = 8.4Hz), 7.451

(m, 3H, J = 26.4Hz), 7.613 (t, 1H, J = 15.6, Ar-H), 7.688 (t, 4H, J = 8.4Hz), 7.782 (td, 1H, J = 10.4Hz, J′ =

2.8Hz), 7.825(dd, 1H, J = 4Hz, J′= 1.6Hz), 8.351 (t, 1H, J = 3.2Hz); 13C-NMR (CDCl3, 100MHz): 77.15, 123.9,

124.23, 125.75, 126.29, 127.36, 128.5, 129.40, 130.72, 133.24, 140.0, 142.4, 160.9, 164.12; IR (KBr, cm-1) (C-

H) 2985, (CH, w) 3352, (C-O) 1195, (C-F) 887, (C-S) 1136 (CH2) - 2787, (NH) 3374; MS(ESI) m/z : 381

[M+H] +; anal. Calculated for C24H16N2OS; C, 75.77; H, 4.24; N, 7.36; O, 4.21; S, 8.43; found C, 75.78; H, 4.25; N, 7.38; O, 4.24; S, 8.44.

2.3.4 2-(4'-Fluoro-biphenyl-2-yl)-5-(5-phenyl-thiophen-2-yl)-[1,3,4]oxadiazole(7d):

Yellow solid; Yield 66%; m. p 132-1330C; 1H- NMR (400MHz, CDCl3): δ 7.080 (t, 2H, J = 17.6Hz), 7.249 (q,

5H), 7.326 (d, 1H, J = 7.2Hz, Ar-H), 7.392 (q, 3H), 7.497 (t, 1H, J = 14.4 Hz), 7.565(m, 3H, J = 12.4Hz), 7.779

(d, 1H, J = 8Hz), 8.125(d, 1H, J = 7.2Hz); 13C-NMR (CDCl3, 100MHz): 21.6, 77.15, 115.3, 122.6, 123.5, 124.0,

126.3, 128.4, 129.5, 130.42, 131.5, 133.1, 136.7, 137.5, 141.0, 143, 149.4, 161.3, 163.8, 182.9; IR (KBr, cm-1)

(C-H) 2965, (CH, w) 3372, (C-O) 1198, (C-F) 889, (C-S) 1146 (CH2) - 2797, (NH) 3394; MS (ESI) m/z : 399

[M+H] +; anal. Calculated for C24H15FN2OS; C, 72.34; H, 3.79; F, 4.77; N, 7.03; O, 4.02; S, 8.05; found C,

72.36; H, 3.80; F, 4.78; N, 7.06; O, 4.04; S, 8.06.

2.3.5 2-(4-Methoxy-phenyl)-5-(5-phenyl-thiophen-2-yl)-[1,3,4]oxadiazole(7e):

Yellow solid; Yield 56%; m. p 142-1480C; 1H- NMR (400MHz, CDCl3): δ 3.893 (s, 3H, OCH3), 7.030 (d, 2H, J

= 9.2Hz), 7.303 (d, 2H, J = 8.4 Hz, Ar-H), 7.37 (d, 1H, J = 4Hz), 7.430 (q, 2H, J = 14.8 Hz), 7.662 (d, 2H, J =

7.2Hz), 7.77 (d, 1H, J = 3.6Hz), 7.811(d, 2H, J = 8.4Hz), 8.059(d, 2H, J = 8.8Hz); 13C-NMR (CDCl3, 100MHz):

21.6, 55.6, 77.15, 114.6, 116.2, 124.0, 126.39, 128.8, 129.5, 130.5, 133.2, 139.2, 143.6, 149.1, 162.5; IR (KBr,

cm-1) (C-H) 2965, (CH, w) 3372, (C-O) 1198, (C-F) 889, (C-S) 1146 (CH2) - 2797, (NH) 3394; MS (ESI) m/z :

399 [M+H] +; anal. Calculated for C19H14N2O2S; C, 68.24; H, 4.22; N, 8.38; O, 9.57; S, 9.59; found C, 68.26; H,

4.24; N, 8.39; O, 9.58; S, 9.60.



1.4 Scheme 1: Synthesis of novel derivatives of 1,3,4-oxadiazole containing 5-phenylthiophene moiety

7a-e:



1.4.1 Figure 2:

1H-NMR and 13 C NMR spectra of the most active compound on Caco-2, 7(b).



2.4.2 Figure 3:

1H-NMR and 13CNMR spectra of the moderately active compound 7 ( e):

Table 1: IC50Values of the Novel Derivatives of 1,3,4-Oxadiazole (7a-e) Containing 5-Phenyl Thiophene

Moiety: SI. No Compounds IC50 Values of 1,3,4-Oxadiazoles 7a-e (µM)

HepG2 (µM)* Caco-2

(µM)*

PANC-1(µM)*

1 7a 67.8 78.9 112.3

2 7b 78.9 5.3* 34.5

3 7c 125.6 56.6 56.8

4 7d 234.5 78.5 123.6

5 7e 28.4 156.7 234.6

6 5-fluouracil 6.7 8.6 7.3

5-fluorouracil-standard used; *potent molecule; IC50: Inhibitory concentration of the compound at 50% of the

cells.

III. Cytotoxic Evaluation (Table 1): 3.1.1 Cell Lines fixation and Culture Conditions:

The in vitro anti-proliferative study was carried out on three human cancer cell lines namely HepG2,

Caco-2 and PANC-1. The cell lines were grown in DMEM-HG supplemented with 10% heat-inactivated FBS,

2% Penicillin-Streptomycin and 2.5 μg/mL Amphotericin-B solutions (All from HI Media Labs, Mumbai,

India). Cell lines were incubated at 37°C in a humidified atmosphere of 95% air, 5% CO2. Following 24-48 hrs of incubation period, the adherent cells were detached using Trypsin-EDTA solution (HI Media Labs, Mumbai,

India). Cell count was done using the Luna automated cell counter (Logos Biosystems, India) based on trypan

blue dye exclusion method. Cytotoxicity of the novel 1, 3, 4-oxadiazoles have been determined using MTT 3-(4,

5-Dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide) assay.

3.1.2 Cell Viability Assay (MTT Assay): The MTT assay was carried out at Genelon Institute of Life Sciences

Pvt. Ltd. 200μL cell suspension was seeded in 96-well microplates (Corning®, USA) at a density of 25,000

cells/well and incubated for 24hrs, all cells were seeded in duplicate with novel compounds 7a-e having range

of concentrations from 50µM-500µM, incubated in a CO2 incubator at 37°C. Treated cells were thereafter

incubated with 10% MTT (5mg/ml; HI Media Labs, Mumbai, India) for 3 hrs.The culture medium was then

aspirated and 200μL dimethyl sulfoxide (DMSO; Sigma-Aldrich, India) was added. 5-Fluoro uracil (5-FU) was used as standard. Cell viability was determined by measuring the absorbance on a micro plate reader

(SPECTRO STAR NANO, BMG LABTECH, Germany) at 570nm. Cell viability was calculated using the

formula [% cell viability = (A570 of treated cells / A570 of control cells) ×100%].

IV. Results And Discussions: 4.1 Chemistry (Scheme 1):In the present work novel derivatives of 1, 3, 4-oxadiazoles 7a-e were synthesized,

characterized and evaluated for their cytotoxicity against HepG2, Caco-2 and PANC-1 cell lines. Synthetic

chemistry involved the conversion of substituted acids into corresponding ester 2a-e. The ester compound was

further converted into corresponding carbohydrazide (IR absorbance of NH 3345 cm-1) 3a-e. The carbohydrazide 3a-e was reacted with 5-phenylthiophene carboxaldehde and obtained Schiff base[17] compounds

6a-e. The Schiff base compounds were cyclized in presence of chloramine–T as promoter and obtained the

novel series of 1,3,4-oxadiazoles 7a-e. The synthesized novel derivatives of 1,3,4-oxadiazole compounds were

evaluated for their cytotoxicity[17, 18] against HepG2, Caco-2 and PANC-1 cell lines using MTT assay.



4.2 b) Anticancer activity (Table 1): The synthesized compounds were screened for in vitro anticancer activity

against three human cancer cell lines[18, 19] namely, HepG2, Caco-2 and PANC-1. The results were expressed in

the form of IC50 (Inhibitory concentration of the compound at 50%). The 5-fluorouracill was used as a standard. The compound (7b) (Fig. 2)showed cytotoxicityagainst human colorectal carcinoma cell line (Caco-2) with IC50

of 5.3µM which is comparable to that of know standard 5-fluorouracil. The compound 7(e) (Fig. 3) showed

moderatecytotoxicity[20] against HepG2 cell line with IC50 of 28.4µM.

V. Conclusion: The cytotoxicity of the synthesized 1,3,4-oxadiazole compounds 7a-e were compared with the

cytotoxicity of the known standard, 5-fluorouracil.Cytotoxicity of the compound 7b (Fig. 2)against Caco-2cell

line with IC50 of 5.3µM which is comparable with the cytotoxicity of the known standard 5-fluorouracil. The

compound 7e (Fig. 3) showed moderate cytotoxicity against HepG2 cell line whose IC50 value is 28.4µM. The authors are interested to study the various biological activities and apoptosis mechanism in their further

research.

Acknowledgements Author is thankful to Mount Carmel College (Autonomous), Bangalore, India. Authors also thank

Mr.Vinod H Naik for the analytical data.

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